Pharmacogenetic Associations with ADME Variants and Virologic Response to an Initial HAART Regimen in HIV-Infected Women

Clinical response to highly active antiretroviral therapy (HAART) varies among different populations. A portion of this variability may be due to variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of HAART.

To identify genetic factors involved in virologic responses to HAART, 13 genes in ADME pathways were analyzed in a cohort of HIV-infected women on HAART. A total of 569 HIV-positive participants from the Women’s Interagency HIV Study who initiated HAART from 1994-2012 and had genotype data were included in these analyses.

Admixture maximum likelihood burden testing was used to evaluate gene-level associations between common genetic variation and virologic response (achieving < 80 viral copies/mL) to HAART overall and with specific drug classes.

Six statistically significant (P < 0.05) gene-level burden tests were observed with response to specific regimen types. CYP2B6, CYP2C19, and CYP2C9 were significantly associated with response to protease inhibitor (PI)-based regimens. CYP2C9, ADH1A, and UGT1A1 were significantly associated with response to triple nucleoside reverse transcriptase inhibitor (NRTI) treatment.

Although no genome-wide associations with virologic response to HAART overall were detected in this cohort of HIV-infected women, more statistically significant gene-level burden tests were observed than would be expected by chance (two and a half expected, six observed).

It is likely that variation in one of the significant genes is associated with virologic response to certain HAART regimens. Further characterization of the genes associated with response to PI-based treatment is warranted.

Morbidity and mortality have declined markedly with the advent and widespread use of highly active antiretroviral therapy (HAART) for individuals with HIV infection. While the primary factor driving response to HAART is adherence, virologic response to HAART varies among adherent individuals and across populations.  Variation in genes that affect the absorption, distribution, metabolism, and excretion (ADME) of antiretrovirals (ARV) is thought to account for a portion of the variability in responses to treatment.

Several studies among HIV-infected individuals have evaluated virologic and immunologic responses, as well as adverse effects such as hypersensitivity reactions, neurotoxicity, hepatotoxicity, and hyperbilirubinemia, in relation to genetic polymorphisms.

The genes which have been most frequently examined in pharmacogenetic association studies in HIV disease include those in the cytochrome p450 family (CYP), as well as the ABCB1 and UGT1A1 genes. The protein products of these genes are reported to be involved in the metabolism and transport of two ARV drug classes, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

Numerous studies have evaluated CYP-based genetic determinants of ARV exposure, but whether these polymorphisms translate to drug efficacy is controversial. There has also been wide interest in the potential genetic influence of ABCB1 on HAART responses owing to the crucial role of P-glycoprotein (encoded by ABCB1) in the distribution and excretion of PIs and NNRTIs.

However, variation in virologic responses to PI-containing regimens in HIV-infected patients who carry variant alleles of two independent ABCB1 polymorphisms has not been consistently observed. Enhanced immunologic recovery in carriers of these ABCB1 variants has been observed in a recent analysis of HIV infected Chinese persons treated with PI-containing regimens (n=275) .

Loss of function alleles in the UGT1A1 gene are associated with drug-related hyperbilirubinemia; carriers of this variant treated with the PI atazanavir develop more severe hyperbilirubinemia, since atazanavir acts as an inhibitor to UGT1A1.

Despite the potential for personalizing HAART regimens based on genetic predictors of response, pharmacogenetic studies of HAART responses to date have not provided conclusive evidence of associations.

Previous pharmacogenetic studies in treated HIV-infected populations have focused on potential functional single nucelotide polymorphisms (SNPs) in genes that metabolize NNRTIs and PIs.

The aim of this study was to comprehensively investigate genetic variation in ADME genes in the Women’s Interagency HIV Study (WIHS), a prospective multi-site observational study of multi-ethnic women infected with HIV, in relationship to virologic response.

This article first published in International Journal of HIV/AIDS and Research  by SciDocPublishers